title: Iptakalim protects against hypoxic brain injury through multiple pathways associated with ATP-sensitive potassium channels.
abstract: The rapid and irreversible brain injury produced by anoxia when stroke occurs is well known. Cumulative evidence suggests that the activation of neuronal ATP-sensitive potassium (KATP) channels may have inherent protective effects during cerebral hypoxia, yet little information regarding the therapeutic effects of KATP channel openers is available. We hypothesized that pretreatment with a KATP channel opener might protect against brain injury induced by cerebral hypoxia. In this study, adult Wistar rats were treated with iptakalim, a new KATP channel opener, which is selective for SUR2 type KATP channels, by intragastric administration at doses of 2, 4, or 8 mg/kg/day for 7 days before being exposed to simulated high altitude equivalent to 8000 m in a decompression chamber for 8 h leading to hypoxic brain injury. By light and electron microscopic images, we observed that hypobaric hypoxia-induced brain injury could be prevented by pretreatment with iptakalim. It was also observed that the permeability of the blood-brain barrier, water content, Na+ and Ca2+ concentration, and activities of Na+,K+-ATPase, Ca2+-ATPase and Mg2+-ATPase in rat cerebral cortex were increased and the gene expression of the occludin or aquaporin-4 was down- or upregulated respectively, which could also be prevented by the pretreatment with iptakalim at doses of 2, 4, or 8 mg/kg in a dose-dependent manner. Furthermore, we found that in an oxygen-and-glucose-deprived model in ECV304 cells and rat cortical astrocytes, pretreatment with iptakalim significantly increased survived cell rates and decreased lactate dehydrogenate release, which were significantly antagonized by glibenclamide, a K(ATP) channel blocker. We conclude that iptakalim is a promising drug that may protect against brain injury induced by acute hypobaric hypoxia through multiple pathways associated with SUR2-type K(ATP) channels, suggesting a new therapeutic strategy for stroke treatment.
authors.affiliation: Department of Environmental Medicine, Tianjin Institute of Hygiene and Environmental Medicine, Tianjin 300050, China.
authors.forename: H-L
authors.initials: HL
authors.lastname: Zhu
authors.forename: W-Q
authors.initials: WQ
authors.lastname: Luo
authors.forename: H
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D001930:Brain Injuries / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002452:Cell Count; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004573:Electrolytes / Q000378:metabolism; D055032:Electron Microscope Tomography / Q000379:methods; D042783:Endothelial Cells / Q000187:drug effects; D002534:Hypoxia, Brain / Q000150:complications / Q000188:drug therapy; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D062793:Occludin; D011437:Propylamines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004573:Electrolytes; D054086:KATP Channels; D008565:Membrane Proteins; C502260:N-(1-methylethyl)-1,1,2-trimethylpropylamine; D018696:Neuroprotective Agents; D062793:Occludin; C568987:Ocln protein, rat; D011437:Propylamines